Supplementary information Molecular insights into

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dbSNP. rsID. CKD-dt. GWAS. SNP. Position. CKD- dt. GWAS. SNP. Chr. Renal eGene. Renal eGene symbol. RTC score. Coloc- alised. 1 rs12124078 15869899.
Supplementary information

Molecular insights into genome-wide association studies of chronic kidney disease-defining traits

Xu et al.

Supplementary table 1. General characteristics of the TRANSLATE study and TCGA.

n Age (years) Men Ethnicity BMI (kg/m2) eGFR (ml/min/1.73m2)

TRANSLATE 180 61.3 (10.7) 99 (55%) white European 27.8 (5.3) 76.2 (20.1)

TCGA 100 61.2 (13.2) 70 (70%) white European NA NA

Data are counts and percenatges or means and standard deviations where appropriate, n - number of individuals, BMI - body mass index, eGFR - estimated glomerular filtration rate. In TRANSLATE Study circulating concentrations of creatinine, were used to calculate eGFR based on the EPI equation [Levey, A. S. et al. A new equation to estimate glomerular filtration rate. Ann. Intern. Med. 150, 604–612 (2009)].

Supplementary table 2. Number of genome-wide association study-pleiotropic or non-pleiotropic eSNPs (single nucleotide variants transcriptionally active in the kidney) stratified upon kidney-specificity (tissue-specific versus ubiquitous). Kidney-specific Non-pleiotropy 5 Pleiotropy 1 Fisher's exact test P-value: 0.0307

Ubiquitous 16 31

Supplementary table 3. Colocalisation analyses.

ID

CKD-dt GWAS SNP dbSNP rsID

CKD-dt GWAS SNP Position

CKDdt GWAS SNP Chr

1 6 6 7 9 13 24 31 34 35 36 52 67 70 73 81 82

rs12124078 rs2049805 rs2049805 rs6677604 rs2802729 rs10206899 rs347685 rs228611 rs12654812 rs7759001 rs2523946 rs3127573 rs4077515 rs10994860 rs2074038 rs626277 rs2928148

15869899 155194980 155194980 196686918 243501763 73900900 141807137 103561709 176794191 27341409 29941943 160681393 139266496 52645424 44087989 72347696 41401550

1 1 1 1 1 2 3 4 5 6 6 6 9 10 11 13 15

83

rs2467853

45698793

15

83 rs2467853 91 rs164748 91 rs164748 91 rs164748 93 rs4227 95 rs11078903 101 rs12458009 107 rs13038305

45698793 89708292 89708292 89708292 7491177 37631924 59350507 23610262

15 16 16 16 17 17 18 20

Renal eGene

Renal eGene symbol

CASP9 ENSG00000132906 GBAP1 ENSG00000160766 MUC1 ENSG00000185499 CFHR1 ENSG00000244414 SDCCAG8 ENSG00000054282 NAT8B ENSG00000204872 TFDP2 ENSG00000114126 ENSG00000246560 RP11-10L12.4 RGS14 ENSG00000169220 ZNF391 ENSG00000124613 HCG4B ENSG00000227262 PLG ENSG00000122194 DNLZ ENSG00000213221 ASAH2B ENSG00000204147 ACCS ENSG00000110455 DACH1 ENSG00000276644 CHP1 ENSG00000187446 CTDENSG00000259520 2651B20.3 SPATA5L1 ENSG00000171763 CHMP1A ENSG00000131165 DPEP1 ENSG00000015413 SPIRE2 ENSG00000204991 SAT2 ENSG00000141504 PGAP3 ENSG00000161395 RNF152 ENSG00000176641 CST9 ENSG00000173335

RTC Colocscore alised

0.93 0.77 0.97 0.55 NA 0.99 0.99 0.90 0.43 0.82 0.32 NA 0.86 0.19 0.99 0.55 NA

Yes No Yes No No Yes Yes Yes No No No No No No Yes No No

0.64

No

0.48 0.62 0.37 0.92 NA 0.51 0.37 0.81

No No No Yes No No No No

ID - internal identifier for each of 117 variants, RTC score - regulatory trait concordance score, NA - the GWAS SNP is located in hotspot hence RTC score could not be obtained, CKD-dt chronic kidney disease and its defining traits, GWAS - genome-wide association study, SNP single nucleotide polymorphism, Chr - Chromosome, eGene - gene whose expression is associated with at least one SNPs

Supplementary table 4. Genomic location, alleles and combined annotation dependant depletion scores for all single nucleotide polymorphisms in the rs2049805 locus. dbSNP rsID

GRCh37 chromosome

GRCh37 position

rs4072037 rs12411216 rs2990245 rs497829 rs2075570 rs2974930 rs2049805 rs914615 rs2974929 rs2974931 rs2066981 rs2974937 rs2990220 rs2974935 rs28445596 rs370545

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

155162067 155164480 155197462 155193532 155182164 155196717 155194980 155175892 155197268 155195215 155172379 155168849 155190254 155181843 155186729 155175390

Reference Alternate allele allele C C C C C A T A T C G C T G T A

T A T G T G C G C G A T A A C G

CADD raw score

Phredscaled CADD score

1.284 0.991 0.759 0.554 0.400 0.288 0.212 0.105 0.061 0.037 -0.154 -0.158 -0.265 -0.378 -0.463 -0.475

12.19 10.61 9.205 7.832 6.611 5.576 4.801 3.664 3.201 2.955 1.359 1.335 0.796 0.438 0.271 0.253

dbSNP rsID - single nucleotide polymorphism database idnetifier, CADD - combined annotation dependant depletion

Supplementary table 5. Assocation between 6 CpG probes proximal to MUC1 promoter and rs12411216 genotype in TRANSLATE study. Probe ID cg03425468 cg07945002 cg12678006 cg09417889 cg15434337 cg27538026

Beta 0.04 0.01 -0.01 0.05 0.02 0.00

Standard error 0.04 0.03 0.02 0.04 0.07 0.06

T-statistic 1.22 0.38 -0.45 1.39 0.29 -0.03

P-value 0.2248 0.7073 0.6511 0.1677 0.7694 0.9774

Beta - linear regression coefficient, SE - standard error, P-value - level of statistical significance

Supplementary table 6. Association between 6 CpG probes proximal to MUC1 promoter and renal expression of MUC1 - TRANSLATE study. Probe ID cg03425468 cg07945002 cg12678006 cg09417889 cg15434337 cg27538026

Beta -57.52 -114.68 49.28 -80.78 -47.11 -53.67

SE 63.33 74.61 96.64 57.59 31.97 35.46

T-statistic -0.91 -1.54 0.51 -1.40 -1.47 -1.51

P-value 0.3665 0.1282 0.6115 0.1645 0.1445 0.1341

Beta - linear regression coefficient, SE - standard error, P-value - level of statistical significance

Supplementary table 7. Average renal expression of MUC1 mRNA isoforms in TRANSLATE study and TCGA. Transcripts are ordered from the most abundant (top) to least abundant (bottom).

Ensembl MUC1 mRNA symbol

Mean expression (transcripts per million)

ENST00000485118 ENST00000612778-as ENST00000612778 ENST00000620103 ENST00000462317 ENST00000468978 ENST00000368392 ENST00000368390 ENST00000368393 ENST00000614519

42.78 36.79 23.15 14.98 10.08 6.05 2.55 1.47 0.66 0.52

Supplementary table 8. Causality between renal expression of total MUC1 and its mRNA isoforms and estimated glomerular filtration rate - robust inverse variance weighted method, Mendelian randomisation-Egger regression (pleiotropy and heterogeneity test). MUC1 isoform

MUC1 isoform symbol

EstimateIVWrobust

P-valueIVWrobust

P-valuepleiotropy

Pvalueheter

ENST00000612778-as ENST00000620103 ENSG00000185499 ENST00000368390 ENST00000612778 ENST00000368392

MUC1-as MUC1-001 MUC1 MUC1-014 MUC1-207 MUC1-002

-0.003 -0.004 -0.014 -0.004 0.002 0.005

2.05E-10 1.91E-08 1.14E-07 7.92E-07 3.84E-05 3.65E-03

0.655 0.740 0.701 0.560 1.000 0.174

0.552 0.514 0.803 0.677 0.383 0.253

as - alternative splicing, IVW - inverse variance weighted method, Estimate-IVW-robust - correlation coefficient from robust IVW method, heter - heterogeneity

Supplementary table 9. Post-imputation genotype quality control applied to imputed variants in the TRANSLATE study and TCGA. TRANSLATE TCGA Imputed variants 47,100,201 47,101,134 Variants mapping to the same genomic position MAF< 5% R2